title: Megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells.
abstract: Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Takeyama
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Taeko
authors.initials: T
authors.lastname: Soma-Nagae
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kabasawa
authors.forename: Akiyo
authors.initials: A
authors.lastname: Suzuki
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto-Kabasawa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hosojima
authors.forename: Reika
authors.initials: R
authors.lastname: Kaneko
authors.forename: Fumie
authors.initials: F
authors.lastname: Higuchi
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kaseda
authors.forename: Shinya
authors.initials: S
authors.lastname: Ogasawara
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3